Citations

ECG Lead I and Outflow Tract ArrhythmiaIntroductionOutflow tract ventricular arrhythmia (OTVA) can be complicated to target for ablation when originating from either the periaortic or pulmonary valve (PV) region. Both sites may present with a small R wave in lead V1. However, the utility of lead I in distinguishing these arrhythmia locations is unknown.Methods and ResultsThirty‐six consecutive patients (mean age 41 ± 14 years, 13 male) underwent catheter ablation for OTVA. OTVA origin was determined from intracardiac electrogram tracings and electroanatomic maps. Observers blinded to results measured QRS waveform amplitude and duration from standard 12‐lead ECG tracings. Measurements with highest diagnostic performance were modeled into an algorithm. Sites of successful ablation were anterior right ventricular outflow tract (RVOT; n = 6), posterior RVOT (n = 4), PV (n = 18), and right coronary cusp (RCC; n = 8). Highest performing surface ECG discriminators were from lead I to V1 vectors: RCC, lead I R wave ≥ 1.5 mV, and V1 R wave ≥2.0 mV (sensitivity 87%, specificity 93%); PV, V1 R wave > 0 mV, and lead I R/(R+S) ≤ 0.75 (sensitivity 78%, specificity 72%); anterior RVOT, V1 R wave = 0 mV, and lead I R/(R+S) <0.4 (sensitivity 67%, specificity 97%); posterior RVOT, V1 R wave > 0 mV, and lead I R/(R+S) > 0.75 (sensitivity 75%, specificity 84%). Sequential algorithmic application of these criteria resulted in an overall accuracy of 72% in predicting site of OTVA origin.ConclusionsA relatively large R wave in lead I is seen with RCC origin but not PV origin. A sequential algorithm has limited but potentially significant value beyond assessment of lead I in approaching OTVA.

Background Neurohormonal dysregulation contributes to heart failure (HF) progression. We sought to determine the effect of cardiac resynchronisation therapy (CRT) on the nerve growth factor (NGF), a biomarker that promotes the maturation, and survival of sympathetic nerve endings, and amino-terminal propeptide of type III procollagen (PIIINP), a marker of type III collagen synthesis. Methods This prospective study enrolled 20 healthy age-matched controls and 45 consecutive patients (pts) who received CRT-D. NYHA class, distance of 6-min walk and echocardiography and plasma concentrations of NGF, PIIINP, b-type natriuretic peptide (BNP), norepinephrine (NE), epinephrine (EPI) and dopamine (DA) were measured before and 6 month after CRT. Response to CRT was defined as ≥15% reduction in left ventricular end-systolic volume index (LVESVI) at 6-month follow-up. Results The baseline BNP (557±692 vs 47±35, p<0.01) and PIIINP (8.22±3.76 vs 5.36±1.47, p<0.01) were elevated in HF compared to controls, while NGF, NE, EPI and DA levels were not different. Twenty two of 45 pts (49%) responded to CRT. The responder group demonstrated significant decrease only in BNP level (p=0.04) at 6-month follow-up, parallelling with the clinical improvements (table 1). The baseline PIIINP was lower in CRT responders than non-responders (p=0.04), and it correlated with the reduction of LVESVI (p=0.01, r=−0.50) after CRT. The further multivariate analysis showed only the plasma PIIINP level among clinic characters and all the biomarkers can predict the improvement of LVESV index (OR=8.33, P=0.01). Conclusion The low PIIINP level, which is consistent with possible less cardiac fibrosis and a more plastic ventricle at baseline, is associated with CRT responsiveness. Contrary to previous reports, the NGF levels were not reduced during HF and that there was no NGF rebound in CRT responders.

ABSTRACT Parkinson's disease (PD) biomarkers are needed to enhance therapeutics research and to understand PD pathogenesis. Methods that simultaneously measure hundreds of small molecular‐weight compounds—metabolomic analysis–“fingerprint” disease‐specific alterations in individual compounds or metabolic pathways. Beyond a nontargeted search for PD biomarkers, we hypothesized that PD cerebrospinal fluid would show increased formation of the excitotoxin 3‐hydroxykynurenine and diminished concentration of the antioxidant glutathione. Cerebrospinal fluid was collected at <4 hours postmortem from 48 pathologically‐verified PD subjects and 57 comparably‐aged controls. Assays involved ultra‐high‐performance liquid and gas chromatography linked to mass spectrometry. We used univariate techniques to determine fold‐changes in concentrations of biochemicals; false‐discovery rates were calculated to exclude spurious findings. Data was modeled using a Support Vector Machine for analyzing compounds selected by Welch's t test. Classification accuracy was determined by cross‐validation. Of 243 structurally‐identified biochemicals,19 compounds differentiated PD from controls at a 20% false‐discovery level. In PD, mean 3‐hydroxykynurenine concentration was increased by one‐third, and mean oxidized glutathione was decreased by 40% (for each, P < .01). Four of the 19 compounds differentiating PD from controls were N‐acetylated amino acids, suggesting a generalized alteration in N‐acetylation activity. The Support Vector Machine classification model distinguished between groups at 83% sensitivity and 91% specificity for the learning data, and at 65% and 79% from cross‐validation. In this study, the first for metabolomic profiling of PD cerebrospinal fluid, we found several novel biomarkers and offer new directions for recognizing disease‐specific biochemical indicators. The findings support involvement of excitotoxicity and oxidative stress in the pathogenesis of PD. © 2013 International Parkinson and Movement Disorder Society

SummaryPre‐existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non‐Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS+) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS−). There were significant baseline differences between the cohorts. CNS+ patients were more likely to be younger, have lower performance scores, higher age‐adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression‐free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS+ group with a subset of CNS− patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n = 55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n = 96) at the time of AHCT. CNS+ patients can achieve excellent long‐term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis.

BackgroundRecent studies have shown that magnetic resonance imaging (MRI) of patients with pacemakers can be safely performed under careful monitoring, but they excluded patients with recently implanted devices. Patients with recent implants may be at a greater risk for complications during MRI imaging due to lack of lead and wound maturity.MethodsWe implemented a clinical protocol for MRI imaging of patients with implanted cardiac devices, and prospectively collected data. For this study, we retrospectively analyzed two groups of patients: those with recently implanted (≤42 days) and nonrecently implanted (>42 days) leads at the time of MRI scanning. All devices were interrogated before and after scanning, and were reprogrammed during the scan as per protocol.ResultsOf the 219 scans (in 171 patients), eight included patients with recently implanted (range: 7–36 days) and 211 with only nonrecently implanted pacemaker leads. During the scan, there were no complications in the early or late group. In one patient imaged 79 days postimplant, frequent premature ventricular complexes were noted during the scan, requiring no action. No patient reported pain during or immediately after the procedure. No clinically significant changes in function were seen at subsequent follow up (average 104 days post‐MRI). Compared to patients with nonrecently implanted leads, there was no difference in any parameter between the two groups.ConclusionsWith a strong clinical indication and with careful monitoring, MRI imaging is feasible in patients with recently implanted pacemakers, although experience is limited.

BackgroundPatients with preexisting mild cognitive impairment or dementia may be at increased risk for developing cardiac device complications due to an impaired ability to follow postimplant care instructions. We sought to determine whether rates of infection, lead dislodgement, or appropriate or inappropriate implantable cardioverter defibrillator (ICD) shocks are increased in this population.MethodsMedical charts of 561 patients with mild cognitive impairment or dementia who underwent pacemaker (PM) or ICD implantation between January 2002 and October 2009 at Mayo Clinic were identified. A total of 134 patients who were diagnosed with cognitive impairment or dementia before device implantation or within 1 year of implantation were compared with 134 matched controls. Information was collected on patient characteristics, comorbid medical conditions, ejection fraction, complications, device type, device therapy, and mortality. Device information was prospectively entered into a database and retrospectively reviewed.ResultsOf the 134 patients with mild cognitive impairment and dementia, 99 underwent PM implantation and 35 underwent ICD implantation. Compared to controls, there was no difference in patient characteristics, ejection fraction, or comorbidities except for diabetes, which was more prevalent in the cognitively impaired and demented group (18.7% vs 30.6%, P = 0.02). There was no difference in device therapy and complications (14.4% vs 5.8%, P = 0.268). However, there was a decreased survival in patients with cognitive impairment and dementia when compared to the control group (42% vs 67% at 5 years, P = 0.007).ConclusionPatients with cognitive impairment and standard device indications are not at increased risk for device complications and therapy but their survival is much lower than in matched controls. The cause of this lower survival is unknown but may be related to the underlying neurological disease. Presence of cognitive impairment should therefore be considered when contemplating implantation of a cardiac device.

Abstract Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer. Mol Cancer Ther; 12(6); 1002–15. ©2013 AACR.

Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

SummaryNuclear factor (NF)-κB is a transcription factor implicated in the pathogenesis of autoimmune disorders such as rheumatoid arthritis (RA). Here we have examined the effect of intra-articular administration of the IKK inhibitor, NEMO-binding domain peptide (NBD), on the severity of collagen-induced arthritis (CIA). NBD peptides were injected intra-articularly into the knee joints of DBA/1J mice after the onset of disease. Collagen-injected mice given a scrambled peptide served as controls. Arthritis severity was determined by visual examination of paws. Intra-articular NBD injection reduced the arthritis score and ameliorated morphological signs of bone destruction compared to the controls. Serum levels of type-II collagen-specific immunoglobulin (Ig)G2a antibodies were lower in NBD-treated mice versus the control mice, whereas the levels of type-II collagen-specific IgG1 antibodies were increased by NBD treatment. NBD treatment diminished the proinflammatory cytokines interleukin (IL)-17 and interferon (IFN)-γ in serum, but increased the regulatory cytokine IL-10. NBD-treated CIA mice exhibited significantly higher percentages and numbers of forkhead box protein 3 (FoxP3+)CD4+CD25+ regulatory T cells than controls. Immunofluorescence analysis of NBD-treated mice revealed that FoxP3 and Ym1, a marker of alternatively activated macrophages, were juxtaposed to each other within draining inguinal lymph nodes. Intra-articular administration of NBD peptide is effective as an experimental therapy in a murine model of RA. Nevertheless, the intra-articular treatment modality is still associated with systemic effects on the immune system.